Transcription factors represent a group of molecules within the cell that function to connect extracellular signals to intracellular responses. Immediately after an environmental stimulus, these proteins which reside predominantly in the cytosol are translocated to the nucleus where they bind to specific DNA sequences in the promoter elements of target genes and activate the transcription of these target genes.
Overexpression or genomic amplification of transcription factor genes can lead to aberrant regulation of cellular processes and consequently to pathologic phenotypes. Studies using comparative genomic hybridization have revealed a number of chromosomal regions of recurrent amplification of copy number in breast tumors while other studies have detected amplification events associated with cancers of the ovary, colon, head and neck, brain and pancreas (Isola et al., Am. J. Pathol., 1995, 147, 905-911; Kallioniemi et al., Proc. Natl. Acad. Sci. U.S.A., 1994, 91, 2156-2160; Kallioniemi et al., Genes Chromosomes Cancer, 1994, 10, 231-243)
Zinc finger protein-217 (also known as ZNF217 and ZABC1) was recently identified as a potential transcription factor that is located in a genomic region of recurrent amplification on chromosome 20q13.2 (Collins et al., Proc. Natl. Acad. Sci. U.S.A., 1998, 95, 8703-8708). Amplification in this chromosomal region has been shown to occur in a variety of tumor types and has been associated with aggressive tumor behavior, especially in invasive breast cancers (Tanner et al., Clin. Cancer Res., 1995, 1, 1455-1461).
Characterization of the protein revealed that zinc finger protein-217 encodes an alternatively spliced protein of either 1062 or 1108 amino acids and contains eight C2H2 zinc finger Kruppel-like DNA-binding motifs. Kruppel-like transcription factors have been implicated in several human malignancies. In addition, the protein contains a proline rich domain and these have been shown to function as transcriptional activators (Collins et al., Proc. Natl. Acad. Sci. U.S.A., 1998, 95, 8703-8708).
The pharmacological modulation of zinc finger protein-217 activity and/or expression is therefore believed to be an appropriate point of therapeutic intervention in pathological conditions. Currently, there are no known therapeutic agents which effectively inhibit the synthesis of zinc finger protein-217 and consequently there remains a long felt need for these agents.
Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of zinc finger protein-217 expression.
The present invention provides compositions and methods for modulating zinc finger protein-217 expression, including modulation of the alternatively spliced form of zinc finger protein-217.